Chemically speaking, thioctic acid (alpha-lipoic acid) is a 1,2-dithiacyclopentane-3-valeric acid. The present invention relates to the racemic form, and also to the pure (R)- or (S)-thioctic acid as well as to mixtures of (R)- and (S)-thioctic acid of any composition. Thioctic acid is a constituent of cell metabolism and is therefore found in many plants and animal organisms. It acts as one of the coenzymes in the oxidative decarboxylation of pyruvate and other alpha-ketoacids. Thioctic acid has been used for a long time in treating various disorders, such as in liver disorders, in liver damage due to mushroom poisoning and in diabetic and alcoholic polyneuropathy, a change in the peripheral nerves associated with metabolic disorders.
Current, commercially available thioctic acid are tablet formulations which contain a maximum of 200 mg thioctic acid in a tablet weighing 515 mg.
To simplify intake and to increase patient acceptance (compliance), there is a need for thioctic acid tablets in higher concentration and smaller size.
Chemically speaking, mesna is the sodium salt of mercaptoethanesulfonic acid. Mesna is used as a mucolytic agent and to prevent bladder toxicity and nephrotoxicity in treatments involving cytostatic agents of the oxazaphosphorin type. In addition to the sodium salt, it is also possible to use the arginine salt described in European Patent EP 198 542.
Flupirtine is used in the form of the maleate to combat pain. Apart from the maleate, it is also possible to use the hydrochloride, the sulphate, the mandelate as well as other pharmaceutically acceptable salts.
The proportional multiplication of the constituents in a tablet containing 200 mg thioctic acid leads, in active ingredient dosages of more than 500 mg per tablet, to tablets having intrinsic weights of more than 1.2 g. Because of their size it is difficult to swallow tablets of such high intrinsic weight, which leads to their poorer acceptance by patients. It would be desirable to reduce the proportion of auxiliary substance in the higher dosed solid medicinal form.
It is, however, impossible to manufacture thioctic acid-containing, mesna-containing or flupirtine-containing tablets with a reduced proportion of active ingredient which are nevertheless of a satisfactory quality, using conventional manufacturing methods.
For example, higher concentrations of thioctic acid lead to tablet pressing problems. The materials to be pressed tend to adhere to the pressing tools. In addition, cracks appear in the tablets parallel to their surface. In the case of biconvex tablets, the domed surface (lid) tends to break away.
These faults are caused by the properties of thioctic acid, the low melting point of the substance of 60.5.degree. C. (R, S-thioctic acid) and 47.degree. C. (R-thioctic acid) and 46.degree. C. (S-thioctic acid) being particularly critical.
The same problems occur when attempts are made to prepare highly concentrated mesna or flupirtine maleate tablets. Tableting defects occur in the case of these active substances, such as adhesion and crack formation when the active ingredient content in the mass to be pressed exceeds 45 weight %. Adhesion to, and smearing of, the pelleting machines are the main problems during pelleting. In addition, pellet masses moistened in conventional manner with conventional auxiliary substances are not bound sufficiently after the finished pellets have been dried.
Published European Patent Application EP-A 420 042 describes the preparation of solid medicinal forms with a high verapamil hydrochloride content through granulation with a small amount of water, the water content being between 2 and 10 weight % in relation to verapamil hydrochloride. Also, in the compulsory second granulation step of the process, the water content is between 2 and 10 weight %.